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Reissued Dec. 14, 1948 I I I s-sltasmnwafifamum t v NewiYork I No Drawing. Original Naamasrawama Au; U gust-10, 1948, Serial No.T672;338,J May25,1945.

,Application for reissu This invention relatesto-newcompounds which are useful as bacterial growth inhibitors or as anti-vitamins for pantothenic acid.

The new compounds are-pantoylalkylamines and related compounds which may be represented .bytheiollowing formula OH; on.

H0H1- J H-C ONHR in which R represents an-alkyl .group containing from 3 to 7 carbon atoms.

The new compounds may be made by the reaction or condensation of alpha, gamma-dihydroxy-beta, beta-dimethyl-butyro1actone or a suitable derivative thereof with an amine having the formula RNH2, where R represents the groupings indicated above.

The amines which can thus be used for reaction or condensation with alpha, gamma-dihydroxy-beta, beta-dimethyl-butyrolactone include alkylamines such as propylamine, ispropylamine, n-butylamine, isobutylamine, sec-butylamine, namylamine, isoamylamine, n-heptylamine, etc.

The new products can be considered N-pantoyl-alkylamines.

The active form of the above compounds is that prepared from ()alpha, gamma-dihydroxybeta, beta-dimethyl-butyrolactone. The racemic lactone forms racemic derivatives with only approximately half the activity (inhibitory properties) of that prepared from the lactone. The methods of preparation may be the same except for purification. The derivatives prepared from the lactone are in general readily purified by vacuum distillation when their melting points are too low for satisfactory recrystallization.

In referring to the new compounds as pantoylalkylamines, etc., the term pantoyl is used for the alpha, gamma-dihydroXy-beta, beta-dimethylbutyryl radical In making the new dl-N-pantoylalkylamines, etc., the dl-pantolactone or dl-alpha, gamma-dihydroxy-beta, beta-dimethlylbutyrolactone is advantageously used with an excess of the calculated quantity of alkylamine, e. g., around 10% excess. The reaction mixture becomes somewhat warm and is then heated with occasional stirring, e. g., at 100 to 110 C. for two hours at atmospheric pressure and for an additional period, e. g., of two hours under reduced pressure to remove the un- 122"Cliiims. (creamer) CPL tsunami-reactants. il he rgmddudt'scan' i casesibe separated sWWwt n tg fiandljffg andrziulithen pnrifletl 'by recrystallization. I "lil heainuerrtion will beiirurfther illustrarted iby iollnwdngzspenxficsexamplesibut it will be under smod ithat ithe filament-1on 1s mot liniited thereto. Thezparizstarrby: weight.

ifEmample -.--2N-- mutoylan pnopylmne .Ginradditmrr ofillt'l2'tpart=6t'm propylamine to I'ZB I parts of rzdl-zailpha-xgamma-dihydroxy beta; beta. dimtl'ryllbflty rdlaotone fiihe :inaxtu're fibecam'e .wmnn. xclt masiheatadtwith occasional stiniingror two hours at 110 C. and the reaction mixture was then heated for two hours under reduced pressure to remove unchanged propylamine. The viscous product showed little tendency to crystallize but a small sample crystallized from petroleum ether-benzene after standing overnight at a low temperature. The remaining product was then crystallized from ether after first being seeded with a small amount of crystalline material. Recrystallization from ether gave colorless octahedral prisms of melting point 454'7 C.

Example II.dl N-pantoylisoamylamine.-To 1.3 parts of dl-pantolactone an excess of 10% over the calculated quantity of isoamylamine was added and the reaction mixture was heated with occasional stirring at -110 C. for about two hours at atmospheric pressure and for an additional two hours under reduced pressure to remove unchanged reactants. On standing overnight the dl-N-pantoylisoamylamine crystallized and was recrystallized from ether containing a small amount of absolute alcohol. The product had a melting point of 76.0-78.0 C.

Example III.dl N pantoylisobuiylamina- This was prepared in accordance with the procedure set forth in Example II but crystallization from the reaction mixture was effected by dissolving in ether and allowing to stand in a refrigerator overnight and by recrystallizing the di- N-pantoylisobutylamine from ether. The crystalline product had a melting point of 65.0-67.0 C.

Example IV.dl-N pantoylisopropylamine.-- This was prepared in accordance with the procedure of the preceding example and the crystalline product had a melting point of 50.5-52.5C.

Example V.-dZ-N-pantoyl-sec butylamine. dl-pantolactone was reacted with sec-butylamine in accordance with the procedure set forth in Example II. Small amounts of the resulting viscous oily material were treated by the addition of petroleum ether and allowed to stand for several days in a refrigerator to form crystals which when added to an ether solution 01' the viscous oily material resulted in crystallization of the d1- N-pantoyl-sec-butylamine which was recrystallized from ether-petroleum ether to give a prodnot having a melting point or 53.( )-56.0 C.

In a similar manner the dl-N-pantoyl-n-butylamine was produced or melting point of 51.6-

%,068 I f l A f? 53.4 C. and the dl-N-pantoyl-n-amylamine of melting point 43.5-450 C.

4 e. g., the pantoyl-n-buty1-, n-amyland n-heptyiamine compounds.

The various compounds vary markedly in inhibitory properties for a single organism; and the relative potencies of members of a series of Compounds differ markedly for different organisms. But'in general all of these compounds inhibit growth of various organisms which require panto- When n-heptylamine was reactedwithdl-pantolactone the resulting product did not crystallize by the methods above referredt'o and was subse quently distilled under a pressure of 10- mm. with an outside bath temperature of 123-128", leaving in this case a liquid product. a

The new compounds above described showed inhibition of growth of several organisms which require pantothenic acid.

The growth inhibiting property of the products I varies with different organisms and with different individual products. In the case of the pantoylalkylamines the compounds containing a normal alkyl group were more active than the isomeric products containing a branched alkyl group against certain organisms. With certain organisms the effectiveness of the pantoylalkylamines increased as the length 01' the alkylgroup increased up to 4 carbon atoms. and then slowly decreased but with other organisms no definite trend in effectiveness with increasing chain-length was apparent. with normal alkylamines containing from-'3 to 7 carbon atoms appear to be particularly valuable,

The .pantoylalkylaminesmade thenic acid for their growth, acting as growth inhibitors or anti-vitamins for pantothenic acid.

We claim: l. New growth inhibiting amides, represented by the following formula:

3H, OH HO oHr-o -oH-0 O-NHR in which R represents an alkyl group containing from 3 to 7 carbon atoms.

, 2. New growth inhibiting amides, represented b'y' the following formula:

110oH,-ocH-c0NH-R HI in which R is a normal alkyl group containing from 3 to '7 carbon atoms.

WILLIAM SHIVE. ESMOND EMERSON SNELL.

No references cited. 

